A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene.
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We have identified a novel fibroblast growth factor receptor 3 (FGFR3) missense mutation in four unrelated individuals with skeletal dysplasia that approaches the severity observed in thanatophoric dysplasia type I (TD1). However, three of the four individuals developed extensive areas of acanthosis nigricans beginning in early childhood, suffer from severe neurological impairments, and have survived past infancy without prolonged life-support measures. The FGFR3 mutation (A1949T: Lys650Met) occurs at the nucleotide adjacent to the TD type II (TD2) mutation (A1948G: Lys650Glu) and results in a different amino acid substitution at a highly conserved codon in the kinase domain activation loop. Transient transfection studies with FGFR3 mutant constructs show that the Lys650Met mutation causes a dramatic increase in constitutive receptor kinase activity, approximately three times greater than that observed with the Lys650Glu mutation. We refer to the phenotype caused by the Lys650Met mutation as "severe achondroplasia with developmental delay and acanthosis nigricans" (SADDAN) because it differs significantly from the phenotypes of other known FGFR3 mutations. (+info)
Markers for bone metabolism in a long-lived case of thanatophoric dysplasia.
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We report a male patient with type 1 thanatophoric dysplasia, now eight years old, having a mutation in the FGFR3 gene. Radiological examination at birth revealed that the ribs and the bones of the extremities were very short and vertebral bodies were greatly reduced in height with wide intervertebral spaces. The femurs were shaped like French telephone receivers. Because of respiratory insufficiency due to the narrow thorax, the patient has been intubated and supported by continuous mechanical ventilation since the day after birth. Since 5 years of age, despite sufficient caloric intake, his body weight never increased above 4700 g, body height 49.0 cm, head circumference 46.1 cm, and chest circumference 35.8 cm. Acanthosis nigricance and huge bilateral coral-like urolithiases has been present. His mental development was severely retarded but he was able to make emotional expressions. Although developments in motor functions could not be assessed, his neurodevelopmental milestones in social relationships and language perception seemed to be at the level of a 10 to 12 month old. His bone maturation was also severely retarded. All of the assays of his serum and urinary bone formation- or resorption-related substances were within normal limits for age. Therefore, bone formation as well as bone resorption activities seemed normal and not responsible for his growth retardation. (+info)
Russell-Silver Syndrome in a Nigerian infant with intrauterine growth retardation.
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Russell-Silver Syndrome (RSS) is a rare cause of pre-natal dwarfism, associated with recognizable dysmorphic features and limb asymmetry. The propositus was a term infant of unrelated Nigerian parents, whose 35-year-old mother had peri-conceptual haloperidol for schizophrenia. Anthropometric values suggested severe prenatal stunting in a term infant with asymmetric "head sparing" intrauterine growth retardation (IUGR). A syndromic consideration of Russell-Silver dwarfism was subsequently predicated on the distinctive dysmorphic craniofacial features of a triangular facial profile with a broad forehead and hypoplastic mandible, right upper and lower limb rhizomelia, clinodactyly of the little fingers, micro-penis, and (unilateral) cryptochidism. Routine care of a small-for-gestational-age infant was pursued, but postnatal growth remained slow (despite adequate caloric provision) until a parent-pressured discharge at 4 weeks. His subsequent demise was said to have occurred "suddenly" 2 weeks post-discharge. Despite the limitations posed by the local paucity of modern investigative tools for genetic disorders, the current case report underscores the diagnostic reality of RSS in a non-white African population. While emphasizing the need for a high index of diagnostic suspicion for congenital malformations and syndromic causes of IUGR in the African sub-region, we suspect a possible etiologic association of haloperidol embryopathy with RSS in the current case. The characteristic features, differential diagnoses, etiologic postulates/current cytogenetic and molecular genetic findings of RSS are fully reviewed in the discussion. (+info)
Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice.
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Several gain-of-function mutations in a receptor tyrosine kinase, fibroblast growth factor receptor 3 (FGFR3), cause dwarfism in humans. Two particularly severe dwarfisms, thanatophoric dysplasia type II (TDII) and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), are associated with glutamic acid (E) and methionine (M) substitutions at the K650 residue in the kinase domain. TDII is lethal at birth, whereas most of the SADDAN patients survive the perinatal period. However, FGFR3 with the SADDAN mutation is more activated than FGFR3 with the TDII mutation in vitro. To find out whether the K650M mutation also causes the SADDAN phenotype, we introduced the corresponding point mutation (K644M) into the mouse Fgfr3 gene. Heterozygous mutant mice show a phenotype similar to human SADDAN, e.g. the majority of the SADDAN mice survive the perinatal period. This suggests that the survival of SADDAN patients is indeed attributed to the K650M mutation in FGFR3. The long bone abnormalities in SADDAN mice are milder than the TDII model. In addition, overgrowth of the cartilaginous tissues is observed in the rib cartilage, trachea and nasal septum. The FGF ligand at the low concentration differentially activates Map kinase in primary chondrocyte cultures from wild-type and SADDAN mice. Comparisons of the molecular bases of the phenotypic differences in SADDAN and TDII mice may increase our understanding of the factors that influence the severity in these two related skeletal dysplasias. (+info)
Diagnosis of skeletal dysplasia by multidisciplinary assessment: a report of two cases of thanatophoric dysplasia.
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Skeletal dysplasias, a heterogeneous group of bone growth disorders, can be detected by routine prenatal ultrasound examination. As it is difficult to make a specific diagnosis, prediction of prognosis is of importance for obstetric management. In order to specify diagnosis, radiological, pathological and molecular genetic examination are often required. Our report describes two cases of thanatophoric dysplasia with different fetal sonographic findings. The classical classification of type I and II seems to be ambiguous as, in both cases, the same mutation in the fibroblast growth factor receptor 3 gene was found. The importance of comprehensive multidisciplinary assessment is emphasized. (+info)
Fetal musculoskeletal malformations with a poor outcome: ultrasonographic, pathologic, and radiographic findings.
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The early and accurate antenatal diagnosis of fetal musculoskeletal malfomations with a poor outcome has important implications for the management of a pregnancy. Careful ultrasonographic examination of a fetus helps detect such anomalies, and a number of characteristic features may suggest possible differential diagnoses. During the last five years, we have encountered 39 cases of such anomalies, and the typical prenatal ultrasonographic and pathologic findings of a number of those are described in this article. (+info)
FGF receptors ubiquitylation: dependence on tyrosine kinase activity and role in downregulation.
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A crucial aspect of ligand-mediated receptor activation and shut-down is receptor internalization and degradation. Here we compared the ubiquitylation of either wild type or a K508A 'kinase-dead' mutant of fibroblast growth factor receptor 3 (FGFR3) with that of its naturally occurring overactive mutants, G380R as in achondroplasia, or K650E involved in thanatophoric dysplasia. Fibroblast growth factor receptors ubiquitylation was found to be directly proportional to their intrinsic tyrosine kinase activity, both of which could be blocked using kinase inhibitors. Despite excessive ubiquitylation, both overactive mutants failed to be efficiently degraded, even when challenged with ligand or overexpression of c-Cbl, a putative E3 ligase. We conclude that phosphorylation is essential for FGFR3 ubiquitylation, but is not sufficient to induce downregulation of its internalization resistant mutants. (+info)
Parathyroid hormone receptor type 1/Indian hedgehog expression is preserved in the growth plate of human fetuses affected with fibroblast growth factor receptor type 3 activating mutations.
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The fibroblast growth factor receptor type 3 (FGFR3) and Indian hedgehog (IHH)/parathyroid hormone (PTH)/PTH-related peptide receptor type 1 (PTHR1) systems are both essential regulators of endochondral ossification. Based on mouse models, activation of the FGFR3 system is suggested to regulate the IHH/PTHR1 pathway. To challenge this possible interaction in humans, we analyzed the femoral growth plates from fetuses carrying activating FGFR3 mutations (9 achondroplasia, 21 and 8 thanatophoric dysplasia types 1 and 2, respectively) and 14 age-matched controls by histological techniques and in situ hybridization using riboprobes for human IHH, PTHR1, type 10 and type 1 collagen transcripts. We show that bone-perichondrial ring enlargement and growth plate increased vascularization in FGFR3-mutated fetuses correlate with the phenotypic severity of the disease. PTHR1 and IHH expression in growth plates, bone-perichondrial rings and vascular canals is not affected by FGFR3 mutations, irrespective of the mutant genotype and age, and is in keeping with cell phenotypes. These results indicate that in humans, FGFR3 signaling does not down-regulate the main players of the IHH/PTHR1 pathway. Furthermore, we show that cells within the bone-perichondrial ring in controls and patients express IHH, PTHR1, and type 10 and type 1 collagen transcripts, suggesting that bone-perichondrial ring formation involves cells of both chondrocytic and osteoblastic phenotypes. (+info)